Source: European Medicines Agency (EU) Revision Year: 2021 Publisher: Janssen-Cilag International NV, Turnhoutseweg 30, B-2340 Beerse, Belgium
Hypersensitivity to the active substance, to risperidone or to any of the excipients listed in section 6.1.
Xeplion should not be used to manage acutely agitated or severely psychotic states when immediate symptom control is warranted.
Caution should be exercised when paliperidone is prescribed in patients with known cardiovascular disease or family history of QT prolongation, and in concomitant use with other medicinal products thought to prolong the QT interval.
Neuroleptic Malignant Syndrome (NMS), characterised by hyperthermia, muscle rigidity, autonomic instability, altered consciousness, and elevated serum creatine phosphokinase levels has been reported to occur with paliperidone. Additional clinical signs may include myoglobinuria (rhabdomyolysis) and acute renal failure. If a patient develops signs or symptoms indicative of NMS, paliperidone should be discontinued.
Medicinal products with dopamine receptor antagonistic properties have been associated with the induction of tardive dyskinesia characterised by rhythmical, involuntary movements, predominantly of the tongue and/or face. If signs and symptoms of tardive dyskinesia appear, the discontinuation of all antipsychotics, including paliperidone, should be considered.
Caution is warranted in patients receiving both, psychostimulants (e.g. methylphenidate) and paliperidone concomitantly, as extrapyramidal symptoms could emerge when adjusting one or both medications. Gradual withdrawal of stimulant treatment is recommended (see section 4.5).
Events of leucopenia, neutropenia, and agranulocytosis have been reported with Xeplion. Agranulocytosis has been reported very rarely (<1/10,000 patients) during post-marketing surveillance. Patients with a history of a clinically significant low white blood cell count (WBC) or a drug-induced leucopenia/neutropenia should be monitored during the first few months of therapy and discontinuation of Xeplion should be considered at the first sign of a clinically significant decline in WBC in the absence of other causative factors. Patients with clinically significant neutropenia should be carefully monitored for fever or other symptoms or signs of infection and treated promptly if such symptoms or signs occur. Patients with severe neutropenia (absolute neutrophil count <1 × 109/L) should discontinue Xeplion and have their WBC followed until recovery.
Anaphylactic reactions in patients who have previously tolerated oral risperidone or oral paliperidone have been rarely reported during post-marketing experience (see sections 4.1 and 4.8).
If hypersensitivity reactions occur, discontinue use of Xeplion; initiate general supportive measures as clinically appropriate and monitor the patient until signs and symptoms resolve (see sections 4.3 and 4.8).
Hyperglycaemia, diabetes mellitus, and exacerbation of pre-existing diabetes including diabetic coma and ketoacidosis, have been reported during treatment with paliperidone. Appropriate clinical monitoring is advisable in accordance with utilised antipsychotic guidelines. Patients treated with Xeplion should be monitored for symptoms of hyperglycaemia (such as polydipsia, polyuria, polyphagia and weakness) and patients with diabetes mellitus should be monitored regularly for worsening of glucose control.
Significant weight gain has been reported with Xeplion use. Weight should be monitored regularly.
Tissue culture studies suggest that cell growth in human breast tumours may be stimulated by prolactin. Although no clear association with the administration of antipsychotics has so far been demonstrated in clinical and epidemiological studies, caution is recommended in patients with relevant medical history. Paliperidone should be used with caution in patients with a pre-existing tumour that may be prolactin-dependent.
Paliperidone may induce orthostatic hypotension in some patients based on its alpha-blocking activity. Based on pooled data from the three placebo-controlled, 6-week, fixed-dose trials with oral paliperidone prolonged release tablets (3, 6, 9, and 12 mg), orthostatic hypotension was reported by 2.5% of subjects treated with oral paliperidone compared with 0.8% of subjects treated with placebo. Xeplion should be used with caution in patients with known cardiovascular disease (e.g. heart failure, myocardial infarction or ischaemia, conduction abnormalities), cerebrovascular disease, or conditions that predispose the patient to hypotension (e.g. dehydration and hypovolemia).
Xeplion should be used cautiously in patients with a history of seizures or other conditions that potentially lower the seizure threshold.
The plasma concentrations of paliperidone are increased in patients with renal impairment and therefore, dose adjustment is recommended in patients with mild renal impairment. Xeplion is not recommended in patients with moderate or severe renal impairment (creatinine clearance <50 mL/min) (see sections 4.2 and 5.2).
No data are available in patients with severe hepatic impairment (Child-Pugh class C). Caution is recommended if paliperidone is used in such patients.
Xeplion has not been studied in elderly patients with dementia. Xeplion should be used with caution in elderly patients with dementia with risk factors for stroke.
The experience from risperidone cited below is considered valid also for paliperidone.
In a meta-analysis of 17 controlled clinical trials, elderly patients with dementia treated with other atypical antipsychotics, including risperidone, aripiprazole, olanzapine, and quetiapine had an increased risk of mortality compared to placebo. Among those treated with risperidone, the mortality was 4% compared with 3.1% for placebo.
An approximately 3-fold increased risk of cerebrovascular adverse reactions has been seen in randomised placebo-controlled clinical trials in the dementia population with some atypical antipsychotics, including risperidone, aripiprazole, and olanzapine. The mechanism for this increased risk is not known.
Physicians should weigh the risks versus the benefits when prescribing Xeplion to patients with Parkinson’s Disease or Dementia with Lewy Bodies (DLB) since both groups may be at increased risk of Neuroleptic Malignant Syndrome as well as having an increased sensitivity to antipsychotics. Manifestation of this increased sensitivity can include confusion, obtundation, postural instability with frequent falls, in addition to extrapyramidal symptoms.
Antipsychotic medicinal products (including risperidone) with alpha-adrenergic blocking effects have been reported to induce priapism. During post-marketing surveillance, priapism has also been reported with oral paliperidone, which is the active metabolite of risperidone. Patients should be informed to seek urgent medical care in case that priapism has not been resolved within 4 hours.
Disruption of the body’s ability to reduce core body temperature has been attributed to antipsychotic medicinal products. Appropriate care is advised when prescribing Xeplion to patients who will be experiencing conditions which may contribute to an elevation in core body temperature, e.g. exercising strenuously, exposure to extreme heat, receiving concomitant medicinal products with anticholinergic activity or being subject to dehydration.
Cases of venous thromboembolism (VTE) have been reported with antipsychotic medicinal products. Since patients treated with antipsychotics often present with acquired risk factors for VTE, all possible risk factors for VTE should be identified before and during treatment with Xeplion and preventative measures undertaken.
An antiemetic effect was observed in preclinical studies with paliperidone. This effect, if it occurs in humans, may mask the signs and symptoms of overdosage with certain medicinal products or of conditions such as intestinal obstruction, Reye’s syndrome and brain tumour.
Care must be taken to avoid inadvertent injection of Xeplion into a blood vessel.
Intraoperative floppy iris syndrome (IFIS) has been observed during cataract surgery in patients treated with medicinal products with alpha 1a-adrenergic antagonist effect, such as Xeplion (see section 4.8).
IFIS may increase the risk of eye complications during and after the operation. Current or past use of medicinal products with alpha 1a-adrenergic antagonist effect should be made known to the ophthalmic surgeon in advance of surgery. The potential benefit of stopping alpha 1 blocking therapy prior to cataract surgery has not been established and must be weighed against the risk of stopping the antipsychotic therapy.
This medicinal product contains less than 1 mmol sodium (23 mg) per dose, i.e. essentially sodium-free.
Caution is advised when prescribing Xeplion with medicinal products known to prolong the QT interval, e.g. class IA antiarrhythmics (e.g. quinidine, disopyramide) and class III antiarrhythmics (e.g. amiodarone, sotalol), some antihistaminics, some other antipsychotics and some antimalarials (e.g. mefloquine). This list is indicative and not exhaustive.
Paliperidone is not expected to cause clinically important pharmacokinetic interactions with medicinal products that are metabolised by cytochrome P-450 isozymes.
Given the primary central nervous system (CNS) effects of paliperidone (see section 4.8), Xeplion should be used with caution in combination with other centrally acting medicinal products, e.g. anxiolytics, most antipsychotics, hypnotics, opiates, etc. or alcohol.
Paliperidone may antagonise the effect of levodopa and other dopamine agonists. If this combination is deemed necessary, particularly in end-stage Parkinson’s disease, the lowest effective dose of each treatment should be prescribed.
Because of its potential for inducing orthostatic hypotension (see section 4.4), an additive effect may be observed when Xeplion is administered with other therapeutic agents that have this potential, e.g. other antipsychotics, tricyclics.
Caution is advised if paliperidone is combined with other medicinal products known to lower the seizure threshold (i.e. phenothiazines or butyrophenones, tricyclics or SSRIs, tramadol, mefloquine, etc.).
Co-administration of oral paliperidone prolonged release tablets at steady-state (12 mg once daily) with divalproex sodium prolonged release tablets (500 mg to 2,000 mg once daily) did not affect the steady-state pharmacokinetics of valproate.
No interaction study between Xeplion and lithium has been performed, however, a pharmacokinetic interaction is not likely to occur.
In vitro studies indicate that CYP2D6 and CYP3A4 may be minimally involved in paliperidone metabolism, but there are no indications in vitro nor in vivo that these isozymes play a significant role in the metabolism of paliperidone. Concomitant administration of oral paliperidone with paroxetine, a potent CYP2D6 inhibitor, showed no clinically significant effect on the pharmacokinetics of paliperidone.
Co-administration of oral paliperidone prolonged release once daily with carbamazepine 200 mg twice daily caused a decrease of approximately 37% in the mean steady-state Cmax and AUC of paliperidone. This decrease is caused, to a substantial degree, by a 35% increase in renal clearance of paliperidone likely as a result of induction of renal P-gp by carbamazepine. A minor decrease in the amount of active substance excreted unchanged in the urine suggests that there was little effect on the CYP metabolism or bioavailability of paliperidone during carbamazepine co-administration. Larger decreases in plasma concentrations of paliperidone could occur with higher doses of carbamazepine. On initiation of carbamazepine, the dose of Xeplion should be re-evaluated and increased if necessary.
Conversely, on discontinuation of carbamazepine, the dose of Xeplion should be re-evaluated and decreased if necessary.
Co-administration of a single dose of an oral paliperidone prolonged release tablet 12 mg with divalproex sodium prolonged release tablets (two 500 mg tablets once daily) resulted in an increase of approximately 50% in the Cmax and AUC of paliperidone, likely as a result of increased oral absorption. Since no effect on the systemic clearance was observed, a clinically significant interaction would not be expected between divalproex sodium prolonged release tablets and Xeplion intramuscular injection. This interaction has not been studied with Xeplion.
Since paliperidone is the major active metabolite of risperidone, caution should be exercised when Xeplion is co-administered with risperidone or with oral paliperidone for extended periods of time. Safety data involving concomitant use of Xeplion with other antipsychotics is limited.
The combined use of psychostimulants (e.g. methylphenidate) with paliperidone can lead to extrapyramidal symptoms upon change of either or both treatments (see section 4.4).
There are no adequate data from the use of paliperidone during pregnancy. Intramuscularly injected paliperidone palmitate and orally administered paliperidone were not teratogenic in animal studies, but other types of reproductive toxicity were seen (see section 5.3). Neonates exposed to paliperidone during the third trimester of pregnancy are at risk of adverse reactions including extrapyramidal and/or withdrawal symptoms that may vary in severity and duration following delivery. There have been reports of agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, or feeding disorder. Consequently, newborns should be monitored carefully. Xeplion should not be used during pregnancy unless clearly necessary.
Paliperidone is excreted in the breast milk to such an extent that effects on the breast-fed infant are likely if therapeutic doses are administered to breast-feeding women. Xeplion should not be used while breast-feeding.
There were no relevant effects observed in the non-clinical studies.
Paliperidone can have minor or moderate influence on the ability to drive and use machines due to potential nervous system and visual effects, such as sedation, somnolence, syncope, vision blurred (see section 4.8). Therefore, patients should be advised not to drive or operate machines until their individual susceptibility to Xeplion is known.
The adverse drug reactions (ADRs) most frequently reported in clinical trials were insomnia, headache, anxiety, upper respiratory tract infection, injection site reaction, parkinsonism, weight increased, akathisia, agitation, sedation/somnolence, nausea, constipation, dizziness, musculoskeletal pain, tachycardia, tremor, abdominal pain, vomiting, diarrhoea, fatigue, and dystonia. Of these, akathisia and sedation/somnolence appeared to be dose-related.
The following are all ADRs that were reported with paliperidone by frequency category estimated from paliperidone palmitate clinical trials. The following terms and frequencies are applied: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000); and not known (cannot be estimated from the available data).
| System Organ Class | Adverse Drug Reaction | ||||
|---|---|---|---|---|---|
| Frequency | |||||
| Very common | Common | Uncommon | Rare | Not knowna | |
| Infections and infestations | upper respiratory tract infection, urinary tract infection, influenza | pneumonia, bronchitis, respiratory tract infection, sinusitis, cystitis, ear infection, tonsillitis, onychomycosis, cellulitis | eye infection, acarodermatitis, subcutaneous abscess | ||
| Blood and lymphatic system disorders | white blood cell count decreased, thrombocytopenia, anaemia | neutropenia, eosinophil count increased | agranulocytosis | ||
| Immune system disorders | hypersensitivity | anaphylactic reaction | |||
| Endocrine disorders | hyperprolactinaemiab | inappropriate antidiuretic hormone secretion, glucose urine present | |||
| Metabolism and nutrition disorders | hyperglycaemia, weight increased, weight decreased, decreased appetite | diabetes mellitusd, hyperinsulinaemia, increased appetite, anorexia, blood triglycerides increased, blood cholesterol increased | diabetic ketoacidosis, hypoglycaemia, polydipsia | water intoxication | |
| Psychiatric disorders | insomniae | agitation, depression, anxiety | sleep disorder, mania, libido decreased, nervousness, nightmare | catatonia, confusional state, somnambulism, blunted affect, anorgasmia | sleep-related eating disorder |
| Nervous system disorders | parkinsonismc, akathisiac, sedation/somnolence, dystoniac, dizziness, dyskinesiac, tremor, headache | tardive dyskinesia, syncope, psychomotor hyperactivity, dizziness postural, disturbance in attention, dysarthria, dysgeusia, hypoaesthesia, paraesthesia | neuroleptic malignant syndrome, cerebral ischaemia, unresponsive to stimuli, loss of consciousness, depressed level of consciousness, convulsione, balance disorder, coordination abnormal | diabetic coma, head titubation | |
| Eye disorders | vision blurred, conjunctivitis, dry eye | glaucoma, eye movement disorder, eye rolling, photophobia, lacrimation increased, ocular hyperaemia | floppy iris syndrome (intraoperative) | ||
| Ear and labyrinth disorders | vertigo, tinnitus, ear pain | ||||
| Cardiac disorders | tachycardia | atrioventricular block, conduction disorder, electrocardiogram QT prolonged, postural orthostatic tachycardia syndrome, bradycardia, electrocardiogram abnormal, palpitations | atrial fibrillation, sinus arrhythmia | ||
| Vascular disorders | hypertension | hypotension, orthostatic hypotension | venous thrombosis, flushing | pulmonary embolism, ischaemia | |
| Respiratory, thoracic and mediastinal disorders | cough, nasal congestion | dyspnoea, respiratory tract congestion, wheezing, pharyngolaryngeal pain, epistaxis | sleep apnoea syndrome, pulmonary congestion, rales | hyperventilation, pneumonia aspiration, dysphonia | |
| Gastrointestinal disorders | abdominal pain, vomiting, nausea, constipation, diarrhoea, dyspepsia, toothache | abdominal discomfort, gastroenteritis, dysphagia, dry mouth, flatulence | pancreatitis, swollen tongue, faecal incontinence, faecaloma, cheilitis | intestinal obstruction, ileus | |
| Hepatobiliary disorders | transaminases increased | gamma- glutamyltransferase increased, hepatic enzyme increased | jaundice | ||
| Skin and subcutaneous tissue disorders | urticaria, pruritus, rash, alopecia, eczema, dry skin, erythema, acne | drug eruption, hyperkeratosis, dandruff | Stevens-Johnson | ||
| Musculoskeletal and connective tissue disorders | musculoskeletal pain, back pain, arthralgia | blood creatine phosphokinase increased, muscle spasms, joint stiffness, muscular weakness, neck pain | rhabdomyolysis, joint swelling | posture abnormal | |
| Renal and urinary disorders | urinary incontinence, pollakiuria, dysuria | urinary retention | |||
| Pregnancy, puerperium and perinatal conditions | drug withdrawal syndrome neonatal (see section 4.6) | ||||
| Reproductive system and breast disorders | amenorrhoea, galactorrhoea | erectile dysfunction, ejaculation disorder, menstrual disordere, gynaecomastia, sexual dysfunction, breast pain | breast discomfort, breast engorgement, breast enlargement, vaginal discharge | priapism | |
| General disorders and administration site conditions | pyrexia, asthenia, fatigue, injection site reaction | face oedema, oedemae, body temperature increased, gait abnormal, chest pain, chest discomfort, malaise, induration | hypothermia, chills, thirst, drug withdrawal syndrome, injection site abscess, injection site cellulitis, injection site cyst, injection site haematoma | body temperature decreased, injection site necrosis, injection site ulcer | |
| Injury, poisoning and procedural complications | fall | ||||
a The frequency of these adverse reactions is qualified as “not known” because they were not observed in paliperidone palmitate clinical trials. They were either derived from spontaneous post-marketing reports and frequency cannot be determined, or they were derived from risperidone (any formulation) or oral paliperidone clinical trials data and/or post-marketing reports.
b Refer to ‘Hyperprolactinaemia’ below.
c Refer to ‘Extrapyramidal symptoms’ below.
d In placebo-controlled trials, diabetes mellitus was reported in 0.32% in Xeplion-treated subjects compared to a rate of 0.39% in placebo group. Overall incidence from all clinical trials was 0.65% in all paliperidone palmitate-treated subjects
e Insomnia includes: initial insomnia, middle insomnia; Convulsion includes: grand mal convulsion; Oedema includes: generalised oedema, oedema peripheral, pitting oedema. Menstrual disorder includes: menstruation delayed, menstruation irregular, oligomenorrhoea
Paliperidone is the active metabolite of risperidone, therefore, the adverse reaction profiles of these compounds (including both the oral and injectable formulations) are relevant to one another.
Rarely, cases of anaphylactic reaction after injection with Xeplion have been reported during post-marketing experience in patients who have previously tolerated oral risperidone or oral paliperidone (see section 4.4).
The most commonly reported injection site related adverse reaction was pain. The majority of these reactions were reported to be of mild to moderate severity. Subject evaluations of injection site pain based on a visual analogue scale tended to lessen in frequency and intensity over time in all Phase 2 and 3 studies with Xeplion. Injections into the deltoid were perceived as slightly more painful than corresponding gluteal injections. Other injection site reactions were mostly mild in intensity and included induration (common), pruritus (uncommon) and nodules (rare).
EPS included a pooled analysis of the following terms: parkinsonism (includes salivary hypersecretion, musculoskeletal stiffness, parkinsonism, drooling, cogwheel rigidity, bradykinesia, hypokinesia, masked facies, muscle tightness, akinesia, nuchal rigidity, muscle rigidity, parkinsonian gait, glabellar reflex abnormal, and parkinsonian rest tremor), akathisia (includes akathisia, restlessness, hyperkinesia, and restless leg syndrome), dyskinesia (dyskinesia, muscle twitching, choreoathetosis, athetosis, and myoclonus), dystonia (includes dystonia, hypertonia, torticollis, muscle contractions involuntary, muscle contracture, blepharospasm, oculogyration, tongue paralysis, facial spasm, laryngospasm, myotonia, opisthotonus, oropharyngeal spasm, pleurothotonus, tongue spasm, and trismus), and tremor. It should be noted that a broader spectrum of symptoms are included that do not necessarily have an extrapyramidal origin.
In the 13-week study involving the 150 mg initiation dosing, the proportion of subjects with an abnormal weight increase ≥7% showed a dose-related trend, with a 5% incidence rate in the placebo group compared with rates of 6%, 8% and 13% in the Xeplion 25 mg, 100 mg, and 150 mg groups, respectively.
During the 33-week open-label transition/maintenance period of the long-term recurrence prevention trial, 12% of Xeplion-treated subjects met this criterion (weight gain of ≥7% from double-blind phase to endpoint); the mean (SD) weight change from open-label baseline was + 0.7 (4.79) kg.
In clinical trials, median increases in serum prolactin were observed in subjects of both genders who received Xeplion. Adverse reactions that may suggest increase in prolactin levels (e.g. amenorrhoea, galactorrhoea, menstrual disturbances, gynaecomastia) were reported overall in <1% of subjects.
QT prolongation, ventricular arrhythmias (ventricular fibrillation, ventricular tachycardia), sudden unexplained death, cardiac arrest, and Torsade de pointes may occur with antipsychotics.
Cases of venous thromboembolism, including cases of pulmonary embolism and cases of deep vein thrombosis, have been reported with antipsychotic medicinal products (frequency unknown).
Reporting suspected adverse reactions after authorisation of the medical product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.
This medicinal product must not be mixed with other medicinal products.
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